Implantable bioartificial perfusion system

ABSTRACT

The disclosure provides an implantable bioartificial active secretion system for providing a physiological regulating secretion such as insulin necessary for functionality of a physiologic activity such as glucose metabolism of a living-being host. The system includes a housing implantable within the host, in fluidic communication with tissue fluid indicative of a physiological regulating secretion need. A chamber within the housing contains a plurality of physiologically active, autonomously functioning, live secretory cells for producing the physiological regulating secretion. A continually operating two pump apparatus moves tissue fluid into contact with the secretory cells for pick up of the physiological regulating secretion for subsequent physiologically-effective dispensing into the host, while avoiding immunorejection of the host body or of the host to the secretory cells.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority under 35 U.S.C. §119(e)to U.S. Provisional Application No. 61/639,078, titled “ImplantableBioartificial Active Insulin Dispenser for Diabetes Control,” filed onApr. 27, 2012, the entire disclosure of which is hereby incorporated byreference in its entirety for all purposes.

FIELD OF THE INVENTION

The present invention relates in general to implantable devices forproviding medically required treatment regimens over a period of time,and in particular to an implantable bioartificial perfusion systemcontaining live secretory cells that provide a physiologically-requiredsecretion to a living-being host patient in response to specificrespective needs of the patient as determined by the live secretorycells in response to physiological make-up of host tissue fluid incontact with the secretory cells.

BACKGROUND OF THE INVENTION

Natural production of numerous agents, metabolites, enzymes, and othersecretions occur within a living being host as physiological events takeplace. One such event is the metabolism of carbohydrates to glucose,which is mainly controlled by insulin produced by the beta cells of theislets of Langerhans within the pancreas. Insulin is necessary inmaintaining glucose homeostasis. In addition to its principal role incarbohydrate metabolism, insulin also significantly affects lipid,protein, and mineral metabolism. When efficient insulin production bythe pancreas is inhibited or terminated and therefore is insufficient,as occurs substantially in Type I diabetes, for example, where immunesystem of the host destroys beta cells of the islets of Langerhans,insulin from another source must be provided or the affected individualwill suffer from many severe consequences of diabetes mellitus. Thedispensation of medicament is determined by live secretory cells inresponse to physiological make-up of host tissue fluid in contact withthe secretory cells. Thus, in the case of a diabetes patient, insulinwould be dispensed whereas chemotherapeutic drugs would be dispensed inthe case of cancer. In these and other similar circumstances, it ishighly beneficial to the patient when automatic dispensing of themedicament occurs, without the need to resort to pills, injections orother discomforting means of medication. A special unit can be implantedwithin the patient. This unit consists of a reservoir of living cells,of type determined by patient's needs, and the live cells act inresponse to the body fluids perfusing through them. The implanted unitwill have a supply of live cells that will be active for 4 years, amicropump and associated electronics to circulate the perfusion fluid, awireless transmitter to communicate with the unit and an inductivelyrechargeable battery.

Prior-art approaches for providing insulin to maintain proper plasmaglucose concentrations are numerous. One of the most commonly employedapproaches is the injection of insulin into the patient a plurality oftimes daily in response to plasma-glucose monitoring. Subcutaneousinjection is a usual insulin introduction route, but is flawed and/ordisfavored for several reasons. In particular, injection administrationis limited because there is no direct feedback between blood glucoselevel and the dosage of insulin. In addition, there is poor patientacceptance, significant absorption variability among patients, potentialoverdosing resulting in hyperinsulinemia/hypoglycemia, potentialunderdosing resulting in hypoinsulinemia/hyperglycemia, formation ofanti-insulin antibodies, hypersensitivity reactions due to insulinformulations, and other untoward occurrences. Relatively new jetinjector devices, as opposed to traditional syringes, do not appreciablyavoid syringe-injection limitations as noted above. Orally administeredinsulin finds poor effectiveness because of the vast variability foundin digestive processes and digestion states among patients.

Another prior art approach for providing insulin to patients is the useof wearable or implantable insulin pumps, which are pre-programmed andpre-loaded with insulin and do not allow direct feedback of the optimaldosage. These pumps can also cause both mechanical and physiologicalproblems for the patient. With respect to the former problem, thesepumps can experience catheter blockage, infection, skin inflammation,erosion, local fluid accumulation, dislocation due to patient physicalactivity, and required regular refills of insulin usually at monthly orbimonthly intervals. With respect to the latter problem, presentlyavailable insulin pumps do not have reliable glucose sensors andtherefore, are unable to precisely dispense a needed insulin quantityfor proper plasma-glucose level maintenance. In addition, presentlyavailable insulin pumps do not have reliable glucose sensors andtherefore, are unable to precisely dispense a needed insulin quantityfor proper plasma-glucose level maintenance.

New methods for treating insulin-dependent diabetes mellitus arepresently being sought. Although it is possible to transplant a pancreasfrom one human to another, the survival rate for this procedure is only40% at one year following surgery. Researchers have also used isolatedpancreatic islets in transplantation approaches in attempts to find aviable long term treatment of diabetes.

The islets of Langerhans are clusters of differentiated cells sharing acommon precursor. Found in the pancreas of mammals, islet cells takentogether can be considered as a single endocrine organ. The islet cellsoccupy about 7% of the human pancreas, which also contains the exocrineacinar tissue. The composition of cells in the islets differ dependingon the location of the islet in the pancreas. Central to each islet is acore of insulin secreting beta cells. Surrounding the beta cells aresomatostatin secreting delta cells, glucagon secreting alpha cells andpancreatic polypeptides containing F-cells. Alpha cells tend to beconcentrated in the tail and the body of the pancreas whereas theF-cells are concentrated in the head. This distribution corresponds tothe embryonic origin of alpha and F-cells from dorsal and ventralprimordium of the pancreas. Transplantation of pancreatic beta cells hasbeen done to the pancreas, liver, muscles, or peritoneal cavity of thepatient, or the transplantation of an entire donor-pancreas as areplacement. Such an approach, however, is not practical because ofrecipient immune-rejection, limited availability of donor organs, andother restraints on patient acceptance.

In view of the above inability of prior art approaches to artificiallyprovide a natural imitation of a physiological secretion, it is apparentthat highly important and unfulfilled needs exist first for sensing anin vivo demand for a secretory product; and second for fulfilling thatrequirement by providing an appropriate quantity of secretory product.

SUMMARY OF THE INVENTION

The present invention addresses these needs and more by providing animplantable bioartificial perfusion system for providing a physiologicalsecretion necessary for the functionality of a physiologic activity of aliving-being host. The system includes a housing having chamber with abiocompatible porous tissue scaffold to maintain the viability andfunctional activity of the cells of the islets of Langerhans, and whichis in fluidic communication with an inlet and an outlet. The inletincludes an external opening thereto, and the outlet includes anexternal opening therefrom. The housing is implantable at leastpartially within the host such that the inlet and outlet openings areplaced in fluidic communication with the tissue fluid of the host. Thetissue fluid can be received into the housing and thereafter dispensedfrom the housing. A chamber is disposed within the housing between theinlet and outlet and in communication therewith, and contains abiocompatible tissue scaffold or similar framework, filled with aplurality of physiologically active, autonomously and in concertfunctioning, live secretory cells for producing the physiologicalsecretion. Also disposed within the housing is a continuously-operatingtwo pump apparatus located upstream and downstream of the chamber fordrawing initial tissue fluid through the inlet from the host for contactwith the physiologically active cells within the chamber for pick up andregulation of the physiological secretion, and for dispensing theresulting tissue fluid bearing the physiological secretion through theoutlet and back into the host. The inlet and outlet filter systems arein operational communication with the external openings of the inlet andoutlet, and have openings therethrough sized for prohibiting passage ofimmune system cells, immunoglobulins, and complement system componentsof the host.

The tissue fluid drawn to be in contact with the live secretory cellsmust generally reflect host requirements for the particularphysiological secretion. Thus, in treating diabetes for example,peritoneal fluid is drawn since it is known that peritoneal fluidreflects blood glucose levels, whereby peritoneal fluid contactssecretory cells that are pancreatic beta cells that produce insulin forperitoneal-fluid uptake and return for routing to regulate glucoselevels. The secretory cells may be immune isolated, using a permeablemedium through which cellular nutrient as well as cellular metabolicwaste can pass and likewise, through which the physiological secretioncan pass, but not through which immune system cells can pass on theoff-chance that such cells may be passed through the inlet filter.Immunoisolation and use of the porous scaffold increases the loadingdensity of the cells and their surface interaction with the fluid aswell as signal communication among cells. Depending upon the specificapplication, secretory-cell life span many times can be up to about fouryears, after which time replacement cells may be introduced.

The two pump apparatus may be located upstream and downstream from thechamber moving there within the initial tissue fluid and the tissuefluid bearing the physiological secretion through the housing.Simultaneously, the arrangement of the plurality of secretory cells issuch that sub-pluralities thereof are disposed on a three-dimensionalscaffold, wherein a plurality of the scaffolds may be situated into apile. To prevent and clean the inlet and outlet nanofilters fromaccumulating and clogging cellular and extracellular matrix material, adouble back flush hydraulic mechanism can be used. The pumping can beaccomplished electromagnetically, by osmotic, electro-osmotic,peristaltic or other pumping methods and may be controlled by aprogrammed controller or special circuit disposed within the housing andthus implanted. The tissue fluid reflects whether a need is present forthe particular secretion provided by the secretory cells (e.g., glucoselevel for insulin-secreting cells), whereby the secretory cells willnaturally respond to the conveyed need and automatically produce aquantity of secretion specific to this need as sensed by the secretorycells. This secretion is picked up by the tissue fluid as it contactsthe secretory cells, and thereafter is delivered within the host. Whenthe tissue fluid indicates less need for the secretion (e.g., therequired activity of the secretion has been completed for the timebeing), such reduced need is sensed by the secretory cells as the tissuefluid continues in contact therewith, and the secretory activitynaturally reduce their secretion or cease until the next demand forsecretion is sensed.

The implantable device, containing a microcontroller and/or otherappropriate circuitry will communicate to the external environment bywireless means. The circuitry will provide data to the host locally on awearable display system as well as have an optional capability to sendinformation over the internet. To reduce bandwidth requirements, thecommunication system will take advantage of data compression or coding.

An optional new application of the self-charging mechanism (employed inelectronic automatic quartz watches) using a weighted rotor to turn atiny electrical generator, charging a rechargeable battery when thepatient with IBPS is moving. The battery powers the control unit, thepump, and circuitry. Alternatively, the electronic control and wirelesscircuits will be powered by mini or micro sized rechargeable batteries.Included in the circuit will be means by which the batteries will beinductively rechargeable, without having to remove the device from thepatient.

A novel miniature pump will provide a constant flow of the peritonealfluid through the IBPS. The pump used for this purpose may be based on avariety of existing pumps and technologies in existence, suchelectroosmotic, dielectrophoretic, micro sized mechanisms,piezoelectrics, etc. Depending on the pump type and action, the pumpsare placed accordingly throughout the system at appropriate locations.In particular, an innovation for this system is the use of a peristalticpump, with no moving parts to perform the peristaltic motion necessaryfor transport of the peritoneal fluid through the system and the pumpsare an integrated part of the scaffold or islet containing base unit.

A miniature glucose sensor will control and assure proper operation. Ifthe concentration of the glucose will be higher than normal level, itwill set off an alarm and the doctor will decide either to increase flowvelocity, or add insulin injections, or replace the implantable device.

A miniature liquid flow sensor will monitor flow rate of a tissue fluidsuch as peritoneal fluid and activate back-flash mechanism viamicroprocessor when the flow rate is below an acceptable level. If theback-flash does not help it will set off an alarm and the doctor shouldreplace the implantable device.

A novel method for islets viability monitoring is a simple, reliable andlong lasting technique based on identification of the critical pH≦7.35signaling death of the islet cells. In this case the doctor shouldimmediately replace the implantable device.

A control circuit with or without wireless capabilities, will monitorand display glucose concentration, pH value and flow velocity on a smallgraphical user interface (GUI) display placed on the patient's wrist Thesame data will also be available to any other device capable ofreceiving data from the implanted unit. The control circuit willautomatically activate the back-flush mechanism and set off an alarm incase of (1) abnormal tissue fluid flow rate; (2) abnormal glucose level;or (3) massive cell death. In the case of massive cell death themicroprocessor will stop the pump in the failed unit and the other unitwill take over. The data will be immediately sent wirelessly to theexternal monitoring devices. When any alarm is triggered, whether from ahigh glucose concentration or massive cell death, or any condition whichis not desirable, the patient should immediately seek medical help froma professional.

As is apparent, the implantable bioartificial perfusion system hereindescribed significantly replicates natural metabolic function byemploying live secretory cells as both sensor and provider ofphysiologic balance. Such live-cell employment eliminates external guesswork with respect to quantity and timing of secretion-product injectionor other type introduction since actual cells make a naturaldetermination of need followed by a natural production and naturalrelease of an exactly-necessary quantity of the secretory product.

BRIEF DESCRIPTION OF THE DRAWINGS

An illustrative embodiment of the invention is shown in the accompanyingdrawings in which:

FIG. 1 is a cross-section view of an implantable bioartificial perfusionsystem implanted into a patient;

FIG. 2 is an illustration of the design and configuration of theexternal inlet tissue fluid sucking filter and external outletnanoporous membrane filter and back-flush mechanism;

FIG. 3 is a view of the wrist, neck or belt wearable GUI display. Theimplant could also be made to communicate with what is currently termeda smart phone.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise defined, scientific and technical terms used inconnection with the disclosure shall have the meanings that are commonlyunderstood by those of ordinary skill in the art. Further, unlessotherwise required by context, singular terms shall include pluralitiesand plural terms shall include the singular. Generally, nomenclaturesutilized in connection with, and techniques of, cell and tissue culture,molecular biology, and protein and oligo- or polynucleotide chemistryand hybridization described herein are those well known and commonlyused in the art. Standard techniques are used for recombinant DNA,oligonucleotide synthesis, and tissue culture and transformation (e.g.,electroporation, lipofection). Enzymatic reactions and purificationtechniques are performed according to manufacturer's specifications oras commonly accomplished in the art or as described herein. Thenomenclatures utilized in connection with, and the laboratory proceduresand techniques of, analytical chemistry, synthetic organic chemistry,and medicinal and pharmaceutical chemistry described herein are thosewell known and commonly used in the art. Standard techniques are usedfor chemical syntheses, chemical analyses, pharmaceutical preparation,formulation, and delivery, and treatment of patients.

In one embodiment, the disclosure provides an implantable bioartificialperfusion system for providing a physiological regulating secretionnecessary for functionality of a physiologic activity of a living-beinghost, the system comprising:

a) a housing having an inlet with an external opening thereto and anoutlet with an external opening therefrom, the housing implantable atleast partially within the host such that the inlet and outlet openingsare placed in fluidic communication with tissue fluid of the host forreceiving into and dispensing from the housing the tissue fluid;

b) a chamber disposed within the housing between the inlet and outletand in communication therewith, the chamber having therein a pluralityof physiologically active, autonomously and in concert functioning, livesecretory cells for producing the physiological secretion;

c) a constantly operating two pump apparatus for drawing initial tissuefluid through the inlet from the host for contact with thephysiologically active cells within the chamber for pick up of thephysiological secretion, and for dispensing resulting tissue fluidbearing the physiological secretion through the outlet and into thehost; and

d) an inlet filter in operational communication with the externalopening of the inlet and disposed upstream of the chamber, wherein theinlet filter comprises a plurality of mesh woven polymer yarn to collectperitoneal fluid from a high surface area of the parietal peritoneum andvisceral peritoneum by means of capillary forces and a size-exclusionmembrane filter separated from the plurality of mesh woven polymer yarnby a capillary gap for prohibiting passage into the chamber of immunesystem cells of the host.

In one aspect, the disclosure provides an implantable bioartificialperfusion system for providing a physiological regulating secretionnecessary for functionality of a physiologic activity of a living-beinghost, wherein the two pump apparatus are located upstream and downstreamfrom the chamber, and wherein the two pump apparatus useselectromagnetic, osmotic, or electro-osmotic force.

In another aspect, the disclosure provides an implantable bioartificialperfusion system for providing a physiological regulating secretionnecessary for functionality of a physiologic activity of a living-beinghost, further comprising an outlet filter in operational communicationwith the external opening of the outlet and disposed downstream of thechamber, wherein the outlet filter comprises pores therethrough sizedfor prohibiting passage into the chamber of immune system cells of thehost.

In another embodiment, the disclosure provides an implantablebioartificial perfusion system for providing a physiological secretionnecessary for functionality of a physiologic activity of a living-beinghost, the system comprising:

a) a housing having an inlet with an external opening thereto and anoutlet with an external opening therefrom, the housing implantable atleast partially within the host such that the inlet and outlet openingsare placed in fluidic communication with peritoneal fluid within aperitoneal cavity of the host for receiving into and dispensing from thehousing the peritoneal fluid;

b) a chamber disposed within the housing between the inlet and outletand in communication therewith, the chamber having therein a pluralityof physiologically active, autonomously and in concert functioning, livesecretory cells for producing the physiological secretion;

c) a constantly operating two pump apparatus disposed for drawinginitial peritoneal fluid through the inlet from the peritoneal cavityfor contact with the physiologically active cells within the chamber forpick up of the physiological secretion, and for dispensing resultingperitoneal fluid bearing the physiological regulating secretion throughthe outlet and into the peritoneal cavity; and

d) an inlet filter in operational communication with the externalopening of the inlet and disposed upstream of the chamber, wherein theinlet filter comprises a tissue fluid sucking filter comprising aplurality of mesh woven polymer yarn and a size-exclusion membranefilter separated from each other by a capillary gap for peritoneal orother tissue fluid collection, filtration and prohibiting passage intothe chamber of immune system agents and cells, immunoglobulins, andcomplement system components of the host.

In one aspect, the disclosure provides an implantable bioartificialperfusion system for providing a physiological secretion necessary forfunctionality of a physiologic activity of a living-being host, whereinthe two pump apparatus are located upstream and downstream from thechamber, and wherein the pump apparatus uses electromagnetic, osmotic,or electro-osmotic force.

In another aspect, the disclosure provides an implantable bioartificialperfusion system for providing a physiological secretion necessary forfunctionality of a physiologic activity of a living-being host, furthercomprising an outlet filter in operational communication with theexternal opening of the outlet and disposed downstream of the chamber,the outlet filter having pores therethrough sized for prohibitingpassage into the chamber of immune system agents, cells,immunoglobulins, and complement system components of the host.

In another embodiment, the disclosure provides an implantablebioartificial perfusion system for providing insulin as necessary forthe metabolism of glucose within a living-being host, the systemcomprising:

a) a housing having an inlet with an external opening thereto and anoutlet with an external opening therefrom, the housing implantable atleast partially within the host such that the inlet and outlet openingsare positionable in fluidic communication with tissue fluid of the hostfor receiving into and dispensing from the housing the tissue fluid;

b) a chamber disposed within the housing between the inlet and outletand in communication therewith, the chamber having stack of severalscaffold, double layer porous mesh matrices, therein a plurality ofphysiologically active, autonomously and in concert functioning, livesecretory cells for producing insulin;

c) a constantly operating two pump apparatus for drawing initial tissuefluid through the inlet from the host for contact with thephysiologically active cells within the chamber for pick up of insulin,and for dispensing the resulting tissue fluid bearing the insulinthrough the outlet and into the host; and

d) an inlet filter in operational communication with the externalopening of the inlet and disposed upstream of the chamber, the inletfilter comprising a tissue fluid sucking filter comprising a pluralityof mesh woven polymer yarn and a size-exclusion membrane filterseparated from each other by a capillary gap for peritoneal or othertissue fluid collection, filtration and prohibiting passage into thechamber of immune system agents and cells, immunoglobulins, andcomplement system components of the host.

In one aspect, the disclosure provides an implantable bioartificialperfusion system for providing insulin as necessary for the metabolismof glucose within a living-being host, wherein the two pump apparatusare located upstream and downstream from the chamber, and wherein thetwo pump apparatus uses electromagnetic, osmotic, or electro-osmoticforce.

In another aspect, the disclosure provides an implantable bioartificialperfusion system for providing insulin as necessary for the metabolismof glucose within a living-being host, further comprising an outletfilter in operational communication with the external opening of theoutlet and disposed downstream of the chamber, the outlet nanoporousmembrane filter having pores therethrough sized for prohibiting passageinto the chamber of immune system cells, immunoglobulins, and complementsystem components of the host.

In another embodiment, the disclosure provides an implantablebioartificial perfusion system for providing insulin necessary forcarbohydrate metabolism within a living-being host, the systemcomprising:

a) a housing having an inlet with an external opening thereto and anoutlet with an external opening therefrom, the housing implantable atleast partially within the host such that the inlet and outlet openingsare positionable in fluidic communication with peritoneal fluid inside aperitoneal cavity of the host for receiving into and dispensing from thehousing the peritoneal fluid;

b) a chamber disposed within the housing between the inlet and outletand in communication therewith, the chamber having stack of severalscaffold, double layer porous mesh matrices, therein a plurality ofphysiologically active, autonomously and in concert functioning, livesecretory cells for producing insulin, wherein the matrices are coatedwith autologous or allogeneic extracellular matrix (ECM) molecules andseeded with a plurality of ECM cells comprising fibroblasts andmacrophages, and wherein two layers of each double matrix are kept at acertain distance from each other by spacers comprising polymermicrospheres coated with ECM molecules;

c) a constantly operating two pump apparatus for drawing initialperitoneal fluid through the inlet from the peritoneal cavity forcontact with the physiologically active cells within the chamber forpick up of regulating insulin, and for dispensing resulting peritonealfluid bearing the insulin through the outlet and into the peritonealcavity; and

d) an inlet filter in operational communication with the externalopening of the inlet and disposed upstream of the chamber, the inletfilter comprising a tissue fluid sucking filter comprising a pluralityof mesh woven polymer yarn and a size-exclusion membrane filterseparated from each other by a capillary gap for peritoneal or othertissue fluid collection, filtration and prohibiting passage into thechamber of immune system agents and cells, immunoglobulins, andcomplement system components of the host.

In one aspect, the disclosure provides an implantable bioartificialperfusion system for providing insulin necessary for carbohydratemetabolism within a living-being host, wherein the two pump apparatusare located upstream and downstream from the chamber and useselectromagnetic, osmotic, or electro-osmotic force or other force by aprogrammed controller disposed within the housing, and wherein theupstream pump apparatus is connected with a back-flush mechanism toclean/dislodge large molecules and/or cells clogging the size-exclusionmembrane filter of the inlet and outlet.

In another aspect, the disclosure provides an implantable bioartificialperfusion system for providing insulin necessary for carbohydratemetabolism within a living-being host, further comprising an outletfilter in operational communication with the external opening of theoutlet and disposed downstream of the chamber, the outlet filter havingnanoporous membrane filter having pores therethrough sized forprohibiting passage into the chamber of immune system agents and cells,immunoglobulins, and complement system components of the host.

In another aspect, the disclosure provides an implantable bioartificialperfusion system for providing insulin necessary for carbohydratemetabolism within a living-being host, wherein the physiologicallyactive secretory cells are pancreatic beta-islet cells provided fromhuman allogenic and/or xenogenic and/or gene development technologysources.

In another aspect, the disclosure provides an implantable bioartificialperfusion system for providing insulin necessary for carbohydratemetabolism within a living-being host, wherein the physiologicallyactive secretory cells are pancreatic islet beta cells.

In another aspect, the disclosure provides an implantable bioartificialperfusion system for providing insulin necessary for carbohydratemetabolism within a living-being host, wherein the controller isprogrammable and regulates administration of the back-flush cycles, andprocesses an alarm signal from a pH sensor followed by turning off thetwo pumps and turning on a sound and vibration alarm.

In another aspect, the disclosure provides an implantable bioartificialperfusion system for providing insulin necessary for carbohydratemetabolism within a living-being host, wherein the controller isintegral with the housing.

In another embodiment, the disclosure provides an implantablebioartificial perfusion system for providing a physiological secretionnecessary for functionality of a physiologic activity of a living-beinghost, the system comprising:

a) a housing having an inlet with an external opening thereto and anoutlet with an external opening therefrom, the housing implantable atleast partially within the host such that the inlet and outlet openingsare positionable in fluidic communication with tissue fluid of the hostfor receiving into and dispensing from the housing the tissue fluid;

b) a chamber disposed within the housing between the inlet and outletand in communication therewith, the chamber having stack of severalscaffold, double layer porous mesh matrices, therein a plurality ofphysiologically active, autonomously and in concert functioning, livesecretory cells for producing insulin, wherein the matrices are coatedwith autologous or allogeneic extracellular matrix (ECM) molecules andseeded with a plurality of ECM cells comprising fibroblasts andmacrophages, and wherein two layers of each double matrix are kept at acertain distance from each other by spacers comprising polymermicrospheres coated with ECM molecules;

c) a constantly operating two pump apparatus for drawing initial tissuefluid through the inlet from the host for contact with thephysiologically active cells within the chamber for pick up of thephysiological secretion, and for dispensing resulting tissue fluidbearing the physiological secretion through the outlet and into thehost; and

d) an inlet filter in operational communication with the externalopening of the inlet and disposed upstream of the chamber, the inletfilter comprising a nanoporous membrane filter having pores therethroughsized for prohibiting passage into the chamber of immune system cells ofthe host.

In one aspect, the disclosure provides an implantable bioartificialperfusion system for providing a physiological secretion necessary forfunctionality of a physiologic activity of a living-being host, whereinthe two pump apparatus are located upstream and downstream from thechamber and uses electromagnetic, osmotic, or electro-osmotic force orother force by a programmed controller disposed within the housing, andwherein the upstream pump apparatus is connected with a back-flushmechanism to clean/dislodge large molecules and/or cells clogging thesize-exclusion membrane filter of the inlet and outlet.

In another aspect, the disclosure provides an implantable bioartificialperfusion system for providing a physiological secretion necessary forfunctionality of a physiologic activity of a living-being host, furthercomprising an outlet filter in operational communication with theexternal opening of the outlet and disposed downstream of the chamber,the outlet filter having nanoporous membrane filter having porestherethrough sized for prohibiting passage into the chamber of immunesystem agents and cells, immunoglobulins, and complement systemcomponents of the host.

In another aspect, the disclosure provides an implantable bioartificialperfusion system for providing a physiological secretion necessary forfunctionality of a physiologic activity of a living-being host, whereinthe physiologically active secretory cells are pancreatic beta-isletcells provided from human allogenic and/or xenogenic and/or genedevelopment technology sources.

FIGS. 1-3 illustrate an embodiment of an implantable bioartificialperfusion system. The following chart summarizes the nonlimitingcomponents of the implantable bioartificial perfusion system:

-   -   Implantable bioartificial perfusion system 8    -   Housing 10    -   Inlet 12    -   External inlet opening 14    -   Outlet 16    -   External outlet opening 18    -   Inlet external filter 20    -   Outlet external filter 22    -   Tissue fluid sucking filter 24    -   Inlet size-exclusion membrane filter 26    -   Capillary gap 28    -   Outlet size-exclusion membrane filter 30    -   Scaffold 32    -   Chamber 34    -   Two pump mechanisms 36    -   Inflow opening 38    -   Outflow opening 40    -   Spacers 42    -   Glucose sensor 44    -   Microprocessor 46    -   GUI display 48    -   Liquid flow sensor 50    -   Back-flush mechanism 52    -   Membrane pH sensor 54    -   Sound and/or vibration alarm 56    -   Shutters 58 and 60    -   Bypass channel 62    -   One-way valve 64    -   Rechargeable battery 66    -   Control unit 74

Referring to FIGS. 1-3, the implantable bioartificial perfusion system 8includes a housing 10 with an inlet 12 with an external inlet opening 14thereto; and an outlet 16 with an external outlet opening 18 therefrom,with inlet 12 and outlet 16 each having an external filter 20 and 22,respectively. The inlet external filter 20 is composed of twocomponents: a tissue fluid sucking filter 24; and a size-exclusionmembrane filter 26, separated from each other by a capillary gap 28. Theoutlet external filter 22 includes a size-exclusion membrane filter 30.The inlet external tissue fluid sucking filter 24 functions as aprefilter that controls the inflow of fluids and has pores/mesh sized toprevent the entry of larger immune cells of the host. Liquids havegenerally unimpeded access through the sucking filter 24. The tissuefluid sucking filter assures collection of the sufficient volume of theperitoneal fluid to feed the implantable bioartificial perfusion systemand provides sufficient filtration of the cellular and humoral agents ofthe host immune system.

The inlet external filter 20 is composed of a tissue fluid suckingfilter 24, made of a bunch or a plurality of mesh woven polymer yarn,and a size-exclusion membrane filter 26, separated from the bunch orplurality of mesh woven polymer yarn by a capillary gap 28 of about25-50 μm, for peritoneal or other tissue fluid collection, filtration,protection against entry of immune system cells, immunoglobulins, andcomplement system components of a host living being. The bunch orplurality of mesh polymer yarn can collect peritoneal fluid from a highsurface area of the peritoneal cavity parietal and visceral wall bymeans of capillary forces and deliver the fluid to the gap 28. Theoutlet external filter 22 includes a size-exclusion membrane filter 30,which may be a nanoporous membrane filter, to prevent immunogenicmaterial of living cells, such as islet of Langerhans cells, in thehousing 10 from leaking from the housing 10 into a host living being.The peritoneal fluid may be filtered through the membrane filter 30 andmoved around the islets of Langerhans cells distributed inside ascaffold 32 in the islet chamber 34 and back to the peritoneal cavitythrough the outlet size-exclusion membrane filter 30 by an action of atwo pump mechanisms 36. Both surfaces of the inlet membrane filter 26and outlet membrane filter 30 may be coated with a protein resistantcoating such as polyethylene glycol, linear poly (methyl glycerol) orlinear polyglycerol. The scaffold 32 for islets allow for closeemulation of the pancreatic environment. In particular, extracellularmatrix (ECM) molecules can support the functional activity of the isletcells. The seeded fibroblasts can secret growth factors stimulatingproliferation and activity of all five types of the islet cells. Seededmacrophages will clean/digest immunogenic material (dead cells andaltered components of the ECM) that can potentially leak into the hostsystem.

The housing 10 and the inlet external filter 20 and the outlet externalfilter 22 may be fabricated of a biocompatible polymer as known in theart.

Disposed within the housing 10 and in fluidic communication with theinlet 12 and outlet 16 is a chamber 34 having an inflow opening 38 andan outflow opening 40. Within the chamber 34 is housed a plurality ofscaffolds 38 having three-dimensional porous matrices or double-layermatrices with spacers 42 there between, such as microspheres and thelike, wherein a plurality of insulin and other hormone secretory cellssuch as provided by islet of Langerhans beta-cells and other isletcells, are disbursed among the stack of several matrices throughout thechamber 34. The scaffolds 32 provide the appropriate biomechanical,biochemical and biological conditions for islet cell proliferation andfunctional activity, uniform islet distribution, sufficient flow of theperitoneal liquid around each of the islets, and constant communicationamong islets. The matrices may be coated with autologous or allogeneicextracellular matrix (ECM) molecules and seeded with a plurality of ECMcells, for example, with fibroblasts and macrophages. The two layers ofthe matrices will be kept at a certain distance from each other byspacers 42 such as microspheres coated with ECM molecules. The pluralityof the matrices enclosing islets will be stacked inside the isletchamber 34. Due to capillary forces of the material of the matrices,islets will be in a constant communication with the flowing peritonealfluid.

Downstream of the chamber 34, is a electromagnetically, electro-osmotic,osmotic or other force driven two pump mechanism 36 for moving fluid(liquid) through the housing 10 and chamber 34 of the implantablebioartificial perfusion system 8. Due to capillary forces of thematerial of the mesh matrices of the scaffolds 32, the secretory cellsare in constant fluidic communication with the moving peritoneal fluid.The two pump mechanisms 36 may be incorporated upstream and downstreamof the chamber 34 to avoid any effect of the disrupted peritoneal fluidflow on the functionality of the islet cells.

The two pump mechanisms 36 provide a constant flow of the peritonealfluid through the implantable bioartificial perfusion system for atleast three years. The two pumps used for this purpose may be based on avariety of existing pumps and technologies in existence, such aselectroosomotic, dielectrophoretic, micro sized mechanisms,piezoelectrics, etc. Depending on the pump type and action, the twopumps may be placed accordingly through the system at appropriatelocations. Also contemplated is the use of one or two peristaltic pumps,with no moving parts to perform peristaltic motions necessary fortransport of the peritoneal fluid through the system. The two pumpmechanism 36 is an integrated part of the scaffold 32 or isletcontaining base unit.

Additionally, the housing 10 may include a miniature glucose sensor 44,such as a miniature amperometric self-powered continuous glucose sensor44 that is placed at the inflow opening 38 of the chamber 34 formonitoring of the glucose concentration in the peritoneal fluid. Thedata may be delivered to the microprocessor 46, optionally with wirelesscapabilities. A glucose sensor 44 will control and assure properoperation of the system. If the concentration of the glucose is higherthan normal level, it will set off an alarm and the doctor will decideeither to increase flow velocity, or add insulin injections, or replacethe implantable device. In case of a high glucose concentration themicroprocessor 46 will first increase the flow rate via the two pumpmechanisms 36 and if this does not help, a sound and vibration alarminside and outside the implantable bioartificial perfusion system on asmall graphical user interface (GUI) display 48.

A wireless GUI display 48 may be placed on a patient's wrist to allowimplementing three levels of the system safety and discriminating amongthe corresponding levels of the alarm urgency. At the first level of theurgency (high glucose concentration in the tissue fluid), a doctor canobserve patient, add lessened doses of the replacement therapy such asinsulin injections, and wait for hormonal, metabolic or other profilestabilization. At the second level of the urgency (reduced flow rate ofthe tissue fluid), the doctor should replace the system because isletare about to die. At the last third level of the urgency (massive deathof islets), the doctor should immediately see the patient to controlpotential hypoglycemia and to replace the system.

Additionally, the housing 10 encloses a miniature liquid flow sensor 50to monitor the flow rate of tissue fluid such as peritoneal fluid flowrate and activate a back-flush mechanism 52 via microprocessor 46 whenthe flow rate is below an acceptable level. A miniature membrane pHsensor 54 may be used to detect a mass death of the islet of Langerhanscells when the pH≦7.35 and shut down the two pump mechanisms 36 and setoff a sound and/or vibration alarm 56. This provides a simple, reliableand long lasting technique based on identification of the criticalpH≦7.35 signaling death of the islet cells. In this case the doctorshould immediately replace the implantable device.

The housing 10 may also encloses an electronic control circuit such as amicroprocessor 46, optionally with wireless capabilities for monitoringof peritoneal fluid glucose level at the inflow opening 38 of thechamber 34, as well as pH value and flow velocity at the outflow opening40 of the chamber 34. The microprocessor 46 may activate the back-flushmechanism 52 when the flow rate drops below an acceptable level and setsoff a sound and/or vibration alarm 56 if the back-flush mechanism 52does not work. Also, the microprocessor 46 can set off a sound and/orvibration alarm 56 if an abnormal glucose level cannot be resolved byincreasing the flow rate of the tissue fluid. Finally, themicroprocessor 46 can set off a sound and/or vibration alarm 56 in caseof the massive cell death of the secretory cells. All normal as well asabnormal data and alarms can be wirelessly (Bluetooth) displayed on thesmall graphical user interface (GUI) display 48 placed on the patient'swrist or other convenient location or device. The GUI display 48 cancommunicate with microprocessor 46 and display an abnormal concentrationof glucose in the peritoneal fluid, an abnormal reduction in the flowrate and a massive death of islets; —all accompanied by a sound andvibration alarm. Bluetooth, standardized as IEEE 802.15.1, is a wirelesstechnology standard for exchanging data over short distances (usingshort-wavelength radio transmissions in the ISM band from 2400-2480 MHz)from fixed and mobile devices creating personal area networks (PANs)with high levels of security. The wireless connection can be one ofseveral types, such us Bluetooth, wi-fi, any type of wirelessconnection, including an induction type of device or other developments.Each device will have a unique ID code so that the data can be uniquelyidentified with a particular patient, especially in the case whereseveral patients, each using the device are in proximity of each other.

For redundancy, the implanted bioartificial perfusion system device isloaded with two to three times more islets than it is needed fortreatment of the recipient's condition.

The housing 10 also encloses a back-flush mechanism 52 to clean/dislodgelarge molecules and/or cells clogging the size-exclusion membranefilters 26 and 30 of the inlet 12 and outlet 16, respectively. Theback-flush mechanism 52 may be composed of a bypass channel 62, and aone-way valve 64 located downstream from the second pump before theoutflow catheter. Periodically (for a short time) the downstream of thechamber pump may be stopped and the upstream of the chamber pump can beput in reverse to deflect the flow of the peritoneal fluid to the bypasschannel 62, thus causing back-flash against inlet filter 26. The fluidflow through the bypass channel 62 produces suction on the outletmembrane filter 30, thus cleaning this filter 30 along with cleaning theinlet filter 26. The back-flush mechanism 52 cleaning of the nanoporoussize-exclusion membrane of the inlet filter 26 and outlet filter 30facilitates delivery of nutrients, oxygen, and glucose to the isletcells and insulin and other hormone distribution from the islet cellsinto the host system with the tissue fluid flow. The back-flushmechanism 52 may be activated by a control unit or microprocessor 46when it receives a signal from a liquid flow sensor 50 indicatingreduction of flow of peritoneal flow rate below an acceptable level.

The housing 10 may further include a self-charging mechanism (employedin electronic automatic quartz watches) that uses a weighted rotor toturn a tiny electrical generator, charging a rechargeable battery 72when the patient with the implantable bioartificial perfusion system 8is moving. The battery 72 powers a control unit 74, and the two pumpmechanisms 36. Alternatively, the electronic control 74 and wirelesscircuits may be powered by a miniature or micro-sized rechargeablebatteries 72. Included in the circuit is a means by which the batteries72 may be inductively rechargeable, without having to remove the devicefrom the patient. Alternatively, or in addition, the electronic control74 and wireless circuits may be powered by a miniature or micro-sizedrechargeable batteries 72. Included in the circuit is a means by whichthe batteries 72 may be inductively rechargeable, without having toremove the device from the patient.

As used herein, the term “biocompatible” includes any material that iscompatible with living tissue or a living system by not being toxic orinjurious and not causing immunological rejection. “Biocompatibility”includes the tendency of a material to be biocompatible. As used herein,the term “biocompatible” refers collectively to both the intact deliverydevice and its contents. Specifically, it refers to the capability ofthe implanted intact delivery device and its contents to avoiddetrimental effects of the body's various protective systems and remainfunctional for a significant period of time. In addition to theavoidance of protective responses from the immune system, or foreignbody fibrotic response, “biocompatible” also implies that no specificundesirable cytotoxic or systemic effects are caused by the deliverydevice and its contents such as would interfere with the desiredfunctioning of the delivery device or its contents. The biocompatibilityof the device is produced by a combination of factors. Of importance forbiocompatibility and continued functionality are bioartificial perfusionsystem morphology, hydrophobicity and the absence of undesirablesubstances either on the surface of, or leachable from, the deliverydevice itself. Thus, brush surfaces, folds, interlayers or other shapesor structures eliciting a foreign body response are avoided. Thebioartificial perfusion system—forming materials are sufficiently purethat unwanted substances do not leach out from the delivery devicematerials themselves.

First, the materials used to form the bioartificial perfusion system aresubstances selected based upon their ability to be compatible with, andaccepted by, the tissues of the recipient of the implanted bioartificialperfusion system. Substances are used which are not harmful to therecipient or to the isolated biologically active cells. Second,substances used in preparing the biocompatible bioartificial perfusionsystem are either free of leachable pyrogenic or otherwise harmful,irritating, or immunogenic substances or are exhaustively purified toremove such harmful substances. Thereafter, and throughout themanufacture and maintenance of the bioartificial perfusion system priorto implantation, great care is taken to prevent the adulteration orcontamination of the bioartificial perfusion system with substanceswhich would adversely affect its biocompatibility. Third, the exteriorconfiguration of the delivery device, including its texture, is formedin such a manner that it provides an optimal interface with the tissuesof the recipient after implantation. This parameter will be defined inpart by the site of implantation. For example, if the delivery devicewill reside in the peritoneal cavity of the recipient, its surfaceshould be smooth. However, if it will be embedded in the soft tissues ofthe recipient, its surface can be moderately rough or stippled. Adetermining factor will be whether it is desirable to allow cells of therecipient to attach to the external surface of the delivery device or ifsuch attachment must be avoided.

A variety of polymers are useful in producing the biocompatible housing,chamber, scaffold and semi-permeable membrane for the nanofilters of thepresent invention. They include, but are not limited to polyalginate,polyvinylchloride, polyvinylidene fluoride, polyurethane isocyanate,cellulose acetate, cellulose diacetate, cellulose triacetate, cellulosenitrate, polysulfone, polystyrene, polyurethane, poly40 vinyl alcohol,polyacrylonitrile, polyamide, polymethylmethacrylate,polytetrafluoroethylene, and polyethylene oxide. In addition, usefulsemi-permeable membranes may be produced from a combination of suchpolymers.

As to the pores size of the nanofilters, delivery devices with poreshaving a molecular weight exclusion of from about 50 kD to about 300 kDmay be useful, with those having pores with a molecular weight cut offof from about 25 kD to about 200 kD also being useful. Other poreconfigurations and/or dimensions are possible without departure from thescope of the present invention.

In an embodiment, the viable cells enclosed within the bioartificialperfusion system are eukaryotic cells, for example, mammalian cells. Anycells that secrete the biologically active agent that is therapeutic toa subject malady may be incorporated into the system of the invention.These cells may be autologous or allogeneic or xenogeneic, or progenitorcells, e.g., stem cells and other pluripotent cells. Additionally oralternatively, cells that secrete a biologically active agent that isprophylactic to a subject malady may be incorporated into the system ofthe invention. Further, any cells which have been genetically engineeredto express a desired active agent, growth factor, and/or their agonists,precursors, derivatives, analogs, or fragments thereof, or other activeagents having similar effector activities may also be useful inpracticing this invention. Additionally, growth factors or growthregulatory substances, and/or a population of feeder or accessory cellsmay be co-isolated within the bioartificial perfusion system. Forexample, beta cells within islets of Langerhans may be co-isolated withfibroblasts accessory cells.

It is contemplated, however, that the bioartificial perfusion system maybe used to deliver into the systemic circulation any molecule that canbe produced and secreted from a viable cell. Although single cell typesthat produce and secrete a single preselected molecule may be used inthe invention, it is understood that cells belonging to a particularcell type that produce and secrete a plurality of preselected moleculeslikewise may be used in the practice of the present invention.Similarly, it is contemplated that a plurality of cell types, whereincells belonging to each cell type produce and secrete differentpreselected molecules, may be combined in the chamber 34 thereby toproduce a device that delivers a desirable combination of preselectedmolecules into the circulation.

An important component of the bioartificial perfusion system includesthe internal cell-supporting matrix or scaffold. The scaffold definesthe microenvironment for the immune-isolated cells, keeps the cells welldistributed within the chamber 34 and provides adequate microcirculationof the tissue fluid. One advantage of the proposed system is its abilityto provide microcirculation of the peritoneal fluid of the host aroundeach “naked” islet along with complete immunoisolation and multi-levelsafety control. The optimal internal scaffold for a particular cellbioartificial perfusion system is highly dependent on the cell type. Forexample, while adherent cells often lie on a solid surface, suspensioncells may lie upon a hydrophilic lightly cross-linked hydrogel as amatrix material.

In the absence of a scaffold, adherent cells aggregate to form clusters.When the clusters grow too large, they typically develop a centralnecrotic core. Dying cells accumulate around the core and, upon lysing,release factors detrimental to the health of neighboring cells. Thelysed cell fragments are also transported to the host environment, thereeliciting an antigenic response.

Several types of prior art devices have attempted to solve theseproblems, meeting with mixed results. For example, the prior artincludes the use of bonded fiber structures for cell implantation (U.S.Pat. No. 5,512,600) and the use of biodegradable polymers as scaffoldsfor organ regeneration such as, for example, liver, pancreas, andcartilage. The use of biodegradable polymers for use as scaffolds inorgan regeneration is reviewed by Cima et al., BIOTECH. BIOENG. 38:145-58 (1991). In these prior art works, biodegradable fiber tassels andfiber-based felts (i.e., non-woven materials) were used as scaffolds fortransplanted cells. One drawback to the use of biodegradable polymers,particularly polymers of poly(lactic acid) PLA, poly(lacticcoglycolicacid) PLGA, poly(glycolic acid) PGA, and their equivalents, is that upondegradation, they release lactic and/or glycolic acid, which are toxicto surrounding tissue. As the polymers degrade, they break down to firstlow molecular weight oligomers and then to the acids, causing a rapidincrease in acid released into the surrounding tissue. This rise in acidconcentration in vivo in the local environment of the implant can inducean inflammatory response or tissue necrosis. Foam scaffolds have alsobeen used in the art to provide surfaces onto which transplanted cellsmay adhere. Foam scaffolds, however, have random flat surfaces and donot provide a linear template for reorganization. Some cell types usesuch a template for organization into physiological three-dimensionalorientation. Prior art also includes woven mesh tubes used as vasculargrafts. Although cells may be seeded onto these woven tubes for improvedbiocompatibility, these tubes function primarily as vascular conduitsand not cell scaffolds. Thus, a need exists in the art for anon-degradable scaffold or framework system to provide an orderedthree-dimensional close to natural environment for cells which use suchan environment to grow and proliferate within bioartificial perfusionsystem.

Certain delivery device geometries have also been found to specificallyelicit foreign body fibrotic responses and should be avoided. Thusdelivery devices should not contain structure having interlayers such asbrush surfaces or folds. In general, opposing delivery device surfacesor edges either from the same or adjacent delivery devices should be atleast 1 mm apart, or greater than 2 mm, or greater than 5 mm. Someembodiments include cylinders, “U”-shaped cylinders, and flat sheets orsandwiches. The surrounding or peripheral region (jacket) of thebiocompatible delivery device can optionally include substances whichdecrease or deter local inflammatory response to the implanted deliverydevice.

An outer housing wall may be a polymer material and may include asurfactant, an anti-inflammatory agent, angiogenic factors, and/or ananti-oxidant. The specific type of polymer, surfactant, or otheradditive may depend on the material to be encapsulated and theconfiguration of the bioartificial perfusion system. Exemplaryanti-inflammatory agents include, but are in no way limited to,corticoids such as cortisone and ACTH, dexamethasone, cortisol,interleukin-1 and its receptor antagonists, and antibodies to TGF-beta,to interleukin-1 (IL-1), and to interferon-gamma. Exemplary surfactantsinclude, but are in no way limited to, Triton-X 100 from SigmaChemicals, and Pluronics P65, P32, and P18. Exemplary anti-oxidantsinclude, but are in no way limited to, vitamin C (ascorbic acid) andvitamin E. Exemplary angiogenic factors include, but are in no waylimited to, fibroblast growth factor and nerve growth factor.

The invention provides an internal filamentous cell-supporting matrix orscaffolding comprising a plurality of filaments, for example, they maybe spun into one or more yarns, or alternatively woven into one or moremesh components. The cell scaffold, in the device of the inventionadvantageously provides cells with a template for cellular organizationin a three-dimensional orientation resembling their typicalphysiological shape.

In one embodiment, the filamentous cell-supporting scaffold is made fromany substantially non degradable biocompatible material. For example,the material can be acrylic, polyester, polyethylene, polypropylene,polyacetonitrile, polyethylene terephthalate, nylon, polyamides,polyurethanes, polybutylester, silk, cotton, chitin, carbon, orbiocompatible metals. The fibers known to the state of the art aresubstantially non-degradable and so do not release by-products into thehost. Moreover, the yarn and mesh matrices used in the invention havethe following advantages over prior art hydrogel matrices: (1) theyprovide a physical surface onto which extracellular matrix molecules maybe attached; (2) they allow adherent cell types to attach and lay downtheir own extracellular matrix material; (3) the yarn or mesh matrix cankeep cells distributed more evenly both longitudinally and transverselyand thus prevent cell clumping which leads to subsequent necrotic coreformation; (4) they offer greater biological stability than hydrogelmaterials and have a long history of implant use as vascular grafts andsuture materials.

In another embodiment, the core scaffold contains a plurality ofmonofilaments. In one example, the monofilaments are twisted into yarn.In another example, the plurality of monofilaments or the yarn is woveninto mesh. In another embodiment, the scaffolding is coated withextracellular matrix (ECM) molecules. Suitable ECM molecules mayinclude, for example, collagen, laminin, and fibronectin. The presentinvention provides several advantages over the prior art. The ECM isseeded with a plurality of cells, which are naturally present in thetissue that is simulated, at minimum with two types of cells:fibroblasts and macrophages. The fibroblasts will reconstitute andmaintain ECM and stimulate growth and proliferation of the main cells.The macrophages will scavenge dead cells and deteriorating material thuspreventing antigenic substances from leaking to the host system. Also,using capillary properties of the woven mesh or 3D polymer scaffoldhaving interconnected network of cells and pores will provide a uniformflow of the tissue fluid around each cell aggregate inside the chamber34. Finally, the scaffold stack will render appropriate biomechanicaland biochemical conditions for islet cells proliferation and functionalactivity.

Operability is here non-limitedly exemplified in the physiologicallybeneficial delivery-on-demand of insulin for glucose metabolism within apatient suffering from Type I diabetes. Particularly, the system housingfunctions in the capacity of an artificial pancreas and is implanted ata site within the peritoneal cavity such that peritoneal fluid can enterthe housing. The housing can be located subcutaneously and be anchoredto the anterolateral region of the iliac crest bone by a bone anchorsystem as known in the art with catheter penetration through theperitoneal fascia and into the peritoneal cavity. This placement permitsrelatively easy, rapid, and complete retrieval in the event of anyimplant failure or malfunction. Implantation into the anterolateralsubcutane abdominal region is carried out under local anesthesia. It isto be noted that peritoneal fluid is chosen for insulin-needdetermination because a change of glucose concentration in peritonealfluid is in the same direction, same amount, and relatively same timefactor as in blood. The peritoneal fluid travels through the inletfilter, inlet opening to the chamber 34 by pumping action of the twopump mechanisms 36 that provides continuous microcirculation of thefluid in contact with insulin secretory cells, which can be present asbeta-cells of islets of Langerhans.

In one embodiment, groups of bare not-encapsulated islets each having adiameter from about 50 to about 200 microns, with total count for theentire chamber of at least about 1,000,000 islets are uniformlydispersed inside porous three-dimensional soft scaffold. Each scaffoldmatrix may be fabricated of biocompatible and stable polymer meshmatrices coated with autologous or allogeneic extracellular matrix (ECM)molecules seeded with a plurality of ECM cells in particularly withfibroblasts and macrophages for housing the secretory cells. The isletswill be distributed either inside pores of each layer of the matrix orbetween two layer of the matrices. The two layers will be kept at acertain distance from each other by spacers such as microspheres coatedwith ECM molecules. The plurality of the single or double matricesenclosing islets will be stacked inside the islet chamber. Movement ofthe peritoneal fluid continues through the chamber for contact with eachporous layer or double layer scaffolds/matrix bearing the insulinsecretory cells, as these secretory cells naturally react to the glucoselevel of the peritoneal fluid and naturally secrete insulin into theperitoneal fluid as determined by the secretory cells to be needed forproper glucose metabolism. Additionally, oxygen and nutrients are passedto the secretory cells while metabolic waste from the secretory cellspasses into the peritoneal fluid. Upon completion of travel through thechamber, the peritoneal fluid moves to the outlet, through the, externaloutlet opening and outlet nanoporous membrane filter for finalreintroduction into the peritoneal cavity and final delivery to thecirculatory system through normal and on-going routing for insulindelivery and use as well as elimination of secretory-cell wasteproducts. Secretory-cell life spans are, of course, dependent upon anumber of factors including proper nutrition and oxygen delivery,appropriate biomechanical and biochemical conditions of the scaffold,waste product removal, and extent of secretion called for by the hostbeing. When cell effectiveness diminishes or ceases, however, theimplantable bioartificial perfusion system is relatively easilyretrieved to be replaced by a new system.

As is apparent from the above description, the perfusion system heredefined bioartificially emulates a naturally occurring secretion systemby providing live secretion-producing cells for sensing and producingsecretions at levels naturally determined because of such liveauthenticity. In addition to such implantation of secretion-producing socells, other media, including drugs, medicines, and/or enzymes, fortreating or preventing diseases in accord with physiological demands,can likewise be administered by employing the system here described andwithin which the chosen media is placed. Thus, while these illustrativeembodiments of the invention have been described in detail herein, it isto be understood that the inventive concepts may be otherwise variouslyembodied and employed and that the appended claims are intended to beconstrued to include such variations except insofar as limited by theprior art.

What is claimed is:
 1. An implantable bioartificial perfusion system forproviding a physiological regulating secretion necessary forfunctionality of a physiologic activity of a living-being host, thesystem comprising: a) a housing having an inlet with an external openingthereto and an outlet with an external opening therefrom, the housingimplantable at least partially within the host such that the inlet andoutlet openings are positionable in fluidic communication with tissuefluid of the host for receiving into and dispensing from the housing thetissue fluid; b) a chamber disposed within the housing between the inletand outlet and in communication therewith, the chamber having therein aplurality of physiologically active, autonomously and in concertfunctioning, live secretory cells for producing the physiologicalregulating secretion; c) a constantly operating two pump apparatus fordrawing initial tissue fluid through the inlet from the host for contactwith the physiologically active cells within the chamber for pick up ofthe physiological regulating secretion, and for dispensing resultingtissue fluid bearing the physiological regulating secretion through theoutlet and into the host; and d) an inlet filter in operationalcommunication with the external opening of the inlet and disposedupstream of the chamber, wherein the inlet filter comprises a pluralityof mesh woven polymer yarn to collect peritoneal fluid from a highsurface area of the parietal peritoneum and visceral peritoneum by meansof capillary forces and a size-exclusion membrane filter separated fromthe plurality of mesh woven polymer yarn by a capillary gap forprohibiting passage into the chamber of immune system cells of the host.2. The implantable bioartificial perfusion system of claim 1, whereinthe two pump apparatus are located upstream and downstream from thechamber, and wherein the two pump apparatus uses electromagnetic,osmotic, or electro-osmotic force.
 3. The implantable bioartificialperfusion system of claim 1, further comprising an outlet filter inoperational communication with the external opening of the outlet anddisposed downstream of the chamber, wherein the outlet filter comprisespores therethrough sized for prohibiting passage into the chamber ofimmune system cells of the host.
 4. An implantable bioartificialperfusion system for providing a physiological regulating secretionnecessary for functionality of a physiologic activity of a living-beinghost, the system comprising: a) a housing having an inlet with anexternal opening thereto and an outlet with an external openingtherefrom, the housing implantable at least partially within the hostsuch that the inlet and outlet openings are positionable in fluidiccommunication with peritoneal fluid within a peritoneal cavity of thehost for receiving into and dispensing from the housing the peritonealfluid; b) a chamber disposed within the housing between the inlet andoutlet and in communication therewith, the chamber having therein aplurality of physiologically active, autonomously and in concertfunctioning, live secretory cells for producing the physiologicalregulating secretion; c) a constantly operating two pump apparatusdisposed for drawing initial peritoneal fluid through the inlet from theperitoneal cavity for contact with the physiologically active cellswithin the chamber for pick up of the physiological regulatingsecretion, and for dispensing resulting peritoneal fluid bearing thephysiological regulating secretion through the outlet and into theperitoneal cavity; and d) an inlet filter in operational communicationwith the external opening of the inlet and disposed upstream of thechamber, wherein the inlet filter comprises a tissue fluid suckingfilter comprising a plurality of mesh woven polymer yarn and asize-exclusion membrane filter separated from each other by a capillarygap for peritoneal or other tissue fluid collection, filtration andprohibiting passage into the chamber of immune system agents and cells,immunoglobulins, and complement system components of the host.
 5. Theimplantable bioartificial perfusion system of claim 4, wherein the twopump apparatus are located upstream and downstream from the chamber, andwherein the two pump apparatus uses electromagnetic, osmotic, orelectro-osmotic force.
 6. The implantable bioartificial perfusion systemof claim 4, further comprising an outlet filter in operationalcommunication with the external opening of the outlet and disposeddownstream of the chamber, the outlet filter having pores therethroughsized for prohibiting passage into the chamber of immune system agents,cells, immunoglobulins, and complement system components of the host. 7.An implantable bioartificial perfusion system for providing insulin asnecessary for the metabolism of glucose within a living-being host, thesystem comprising: a) a housing having an inlet with an external openingthereto and an outlet with an external opening therefrom, the housingimplantable at least partially within the host such that the inlet andoutlet openings are positionable in fluidic communication with tissuefluid of the host for receiving into and dispensing from the housing thetissue fluid; b) a chamber disposed within the housing between the inletand outlet and in communication therewith, the chamber having stack ofseveral scaffold, double layer porous mesh matrices, therein a pluralityof physiologically active, autonomously and in concert functioning, livesecretory cells for producing insulin; c) a constantly operating twopump apparatus for drawing initial tissue fluid through the inlet fromthe host for contact with the physiologically active cells within thechamber for pick up of insulin, and for dispensing the resulting tissuefluid bearing the insulin through the outlet and into the host; and d)an inlet filter in operational communication with the external openingof the inlet and disposed upstream of the chamber, the inlet filtercomprising a tissue fluid sucking filter comprising a plurality of meshwoven polymer yarn and a size-exclusion membrane filter separated fromeach other by a capillary gap for peritoneal or other tissue fluidcollection, filtration and prohibiting passage into the chamber ofimmune system agents and cells, immunoglobulins, and complement systemcomponents of the host.
 8. The implantable bioartificial perfusionsystem of claim 7, wherein the two pump apparatus are located upstreamand downstream from the chamber, and wherein the two pump apparatus useselectromagnetic, osmotic, or electro-osmotic force.
 9. The implantablebioartificial perfusion system of claim 7, further comprising an outletfilter in operational communication with the external opening of theoutlet and disposed downstream of the chamber, the outlet nanoporousmembrane filter having pores therethrough sized for prohibiting passageinto the chamber of immune system cells, immunoglobulins, and complementsystem components of the host.
 10. An implantable bioartificialperfusion system for providing insulin necessary for carbohydratemetabolism within a living-being host, the system comprising: a) ahousing having an inlet with an external opening thereto and an outletwith an external opening therefrom, the housing implantable at leastpartially within the host such that the inlet and outlet openings arepositionable in fluidic communication with peritoneal fluid inside aperitoneal cavity of the host for receiving into and dispensing from thehousing the peritoneal fluid; b) a chamber disposed within the housingbetween the inlet and outlet and in communication therewith, the chamberhaving stack of several scaffold, double layer porous mesh matrices,therein a plurality of physiologically active, autonomously and inconcert functioning, live secretory cells for producing insulin, whereinthe matrices are coated with autologous or allogeneic extracellularmatrix (ECM) molecules and seeded with a plurality of ECM cellscomprising fibroblasts and macrophages, and wherein two layers of eachdouble matrix are kept at a certain distance from each other by spacerscomprising polymer microspheres coated with ECM molecules; c) aconstantly operating two pump apparatus for drawing initial peritonealfluid through the inlet from the peritoneal cavity for contact with thephysiologically active cells within the chamber for pick up ofregulating insulin, and for dispensing resulting peritoneal fluidbearing the insulin through the outlet and into the peritoneal cavity;and d) an inlet filter in operational communication with the externalopening of the inlet and disposed upstream of the chamber, the inletfilter comprising a tissue fluid sucking filter comprising a pluralityof mesh woven polymer yarn and a size-exclusion membrane filterseparated from each other by a capillary gap for peritoneal or othertissue fluid collection, filtration and prohibiting passage into thechamber of immune system agents and cells, immunoglobulins, andcomplement system components of the host.
 11. The implantablebioartificial perfusion system of claim 10, wherein the two pumpapparatus are located upstream and downstream from the chamber and useselectromagnetic, osmotic, or electro-osmotic force or other force by aprogrammed controller disposed within the housing, and wherein theupstream pump apparatus is connected with a back-flush mechanism toclean/dislodge large molecules and/or cells clogging the size-exclusionmembrane filter of the inlet and outlet.
 12. The implantablebioartificial perfusion system of claim 10, further comprising an outletfilter in operational communication with the external opening of theoutlet and disposed downstream of the chamber, the outlet filter havingnanoporous membrane filter having pores therethrough sized forprohibiting passage into the chamber of immune system agents and cells,immunoglobulins, and complement system components of the host.
 13. Theimplantable bioartificial perfusion system of claim 10, wherein thephysiologically active secretory cells are pancreatic beta-islet cellsprovided from human allogenic and/or xenogenic and/or gene developmenttechnology sources.
 14. The implantable bioartificial perfusion systemof claim 10, wherein the physiologically active secretory cells arepancreatic islet beta cells.
 15. The implantable bioartificial perfusionsystem of claim 11, wherein the controller is programmable and regulatesadministration of the back-flush cycles, and processes an alarm signalfrom a pH sensor followed by turning off the pump and turning on a soundand vibration alarm.
 16. The implantable bioartificial perfusion systemof claim 16, wherein the controller is integral with the housing.
 17. Animplantable bioartificial perfusion system for providing a physiologicalregulating secretion necessary for functionality of a physiologicactivity of a living-being host, the system comprising: a) a housinghaving an inlet with an external opening thereto and an outlet with anexternal opening therefrom, the housing implantable at least partiallywithin the host such that the inlet and outlet openings are positionablein fluidic communication with tissue fluid of the host for receivinginto and dispensing from the housing the tissue fluid; b) a chamberdisposed within the housing between the inlet and outlet and incommunication therewith, the chamber having stack of several scaffold,double layer porous mesh matrices, therein a plurality ofphysiologically active, autonomously and in concert functioning, livesecretory cells for producing insulin, wherein the matrices are coatedwith autologous or allogeneic extracellular matrix (ECM) molecules andseeded with a plurality of ECM cells comprising fibroblasts andmacrophages, and wherein two layers of each double matrix are kept at acertain distance from each other by spacers comprising polymermicrospheres coated with ECM molecules; c) a constantly operating twopump apparatus for drawing initial tissue fluid through the inlet fromthe host for contact with the physiologically active cells within thechamber for pick up of the physiological regulating secretion, and fordispensing resulting tissue fluid bearing the physiological regulatingsecretion through the outlet and into the host; and d) an inlet filterin operational communication with the external opening of the inlet anddisposed upstream of the chamber, the inlet filter comprising ananoporous membrane filter having pores therethrough sized forprohibiting passage into the chamber of immune system cells of the host.18. The implantable bioartificial perfusion system of claim 17, whereinthe two pump apparatus are located upstream and downstream from thechamber and uses electromagnetic, osmotic, or electro-osmotic force orother force by a programmed controller disposed within the housing, andwherein the upstream pump apparatus is connected with a back-flushmechanism to clean/dislodge large molecules and/or cells clogging thesize-exclusion membrane filter of the inlet and outlet.
 19. Theimplantable bioartificial perfusion system of claim 17, furthercomprising an outlet filter in operational communication with theexternal opening of the outlet and disposed downstream of the chamber,the outlet filter having nanoporous membrane filter having porestherethrough sized for prohibiting passage into the chamber of immunesystem agents and cells, immunoglobulins, and complement systemcomponents of the host.
 20. The implantable bioartificial perfusionsystem of claim 17, wherein the physiologically active secretory cellsare pancreatic beta-islet cells provided from human allogenic and/orxenogenic and/or gene development technology sources.